The sense of taste is mediated by multicellular taste buds, which are located in epithelial-mesenchymal structures on the tongue known as gustatory papillae. Three morphologically distinct types of gustatory papillae (fungiform, foliate, and circumvallate) are found in specific regions on the dorsal surface of the tongue. The circumvallate papilla (CVP) is a complex gustatory structure, housing several hundred taste buds within its epithelial trenches, which are contiguous with secretory gland epithelia. Despite the large literature on the function and structure of the CVP and its resident taste buds in adults, much remains to be discovered about its embryonic development. Interestingly, while humans have several CVPs, mice have only one, located at the midline of the posterior tongue. The mechanisms that control CVP number in different species are not known. Sprouty2 (Spry2), which encodes an antagonist of receptor tyrosine kinase (RTK) signaling, functions in the development of a number of tissues. For example, Spry2 regulates the Fibroblast Growth Factor (FGF) pathway in tooth development, such that inactivation of Spry2 results in formation of additional teeth as a consequence of upregulation of FGF signaling. We have recently found that inactivation of Spry2 also leads to duplication of the CVP in mice, and this duplication event can be detected at the earliest stages of CVP development. Specifically, by embryonic day (E)12.5, when the CVP placode is morphologically detectable in whole-mount, the Spry2 mutant CVP placode is markedly larger than the wild-type. This novel mutant phenotype suggests that Spry2 functions at the earliest stages of CVP placode development to restrict the size of the taste organ progenitor field and thus prevent formation of supernumerary taste papillae. In this application, we propose to test the hypothesis that Sprouty genes function downstream of FGFs and/or other secreted factors to regulate cell behaviors, which in turn restricts the presumptive CVP domain and ensures formation of the proper number of circumvallate papillae. Successful completion of these studies is important for issues of human health related to taste function, as well as more generally to enhance knowledge of embryonic development and its regulation by growth factors. PUBLIC HEALTH RELEVANCE: The taste system is the primary sensory mechanism that determines whether a food or beverage will be consumed. Learning how this system develops and functions is critical for understanding why patients with conditions such as obesity over-consume and why patients such as those who are receiving chemotherapy under-consume. Thus, knowledge about the molecular pathways controlling taste development is of major clinical importance, and the experiments in this R21 application will enhance our knowledge of these pathways.